2,6-diamino-4-pyrimidinylamine -Drug Synthesis Database

【结构式】

【分子编号】28977

【品名】2,6-diamino-4-pyrimidinylamine

【CA登记号】1004-38-2

【分子式】C₄H₇N₅

【分子量】125.13328

【元素组成】C 38.39% H 5.64% N 55.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

The reaction of 2,5-dimethoxybenzaldehyde (I) with ethyl acetoacetate (II) in a mixture of piperidine and glacial acetic acid in refluxing benzene gives ethyl alpha-acetyl-beta-(2,5-dimethoxyphenyl)acrylate (III), which is hydrogenated in a Parr low-pressure apparatus using 5% palladium on charcoal catalyst in ethyl acetate to yield ethyl alpha-acetyl-(2,5-dimethoxyphenyl)propionate (IV). The condensation of the propionate (IV) with 2,4.6-triaminopyrimidine in diphenylether at 195-230 C provides 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (VI). The key intermediate (VI) is converted to the 7-chloro compound (VII) by treatment with a 1:1 complex of N,N-dimethylformamide thionyl chloride, and finally (VII) is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield BW-301 U.

参考文献中间体

合成目标

【1】 Grivsky, E.M.; et al.; Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. J Med Chem 1980, 23, 3, 327-329.
【2】 Sigel, C.W.; BW-301 U. Drugs Fut 1985, 10, 2, 108.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10174	2,5-Dimethoxybenzaldehyde	93-02-7	C₉H₁₀O₃	详情	详情
(II)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(III)	28975	ethyl (Z)-2-acetyl-3-(2,5-dimethoxyphenyl)-2-propenoate		C₁₅H₁₈O₅	详情	详情
(IV)	28976	ethyl 2-(2,5-dimethoxybenzyl)-3-oxobutanoate		C₁₅H₂₀O₅	详情	详情
(V)	28977	2,6-diamino-4-pyrimidinylamine	1004-38-2	C₄H₇N₅	详情	详情
(VI)	28978	2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₁₇H₁₉N₅O₃	详情	详情
(VII)	28979	2-amino-7-chloro-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-4-ylamine		C₁₇H₁₈ClN₅O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

In an alternative synthesis, 2,4,6-triaminopyrimidine (VI) was condensed with bromomalonaldehyde (VII) under acidic conditions to give pyridopyrimidine (VIII), which was protected with pivaloyl anhydride in pyridine, yielding the bispivaloylamide (IX). Palladium-catalyzed Heck coupling of (IX) with styrene (X) afforded (XI). Subsequent ozonolysis of the styryl derivative (XI), followed by reductive workup with dimethyl sulfide gave aldehyde (XII). Reduction of (XII) to the corresponding alcohol with NaBH4, followed by bromination with PPh3 and Br2 provided bromide (XIII). The N-methyl aniline (XIV) was synthesized by direct alkylation of 3,4,5-trimethoxyaniline (IV) with methyl iodide. Nucleophilic displacement of the bromide (XIII) with aniline (XIV) afforded the tertiary amine (XV). The pivaloyl protecting groups of (XV) were finally removed by treatment with methanolic NaOMe.

参考文献中间体

合成目标

【1】 Gangjee, A.; et al.; Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5, 10-dideaza lipophilic antifolates. J Med Chem 1997, 40, 4, 470.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情
(VI)	28977	2,6-diamino-4-pyrimidinylamine	1004-38-2	C₄H₇N₅	详情	详情
(VII)	14278	2-Bromomalonaldehyde		C₃H₃BrO₂	详情	详情
(VIII)	31547	6-bromopyrido[2,3-d]pyrimidine-2,4-diamine; 2-amino-6-bromopyrido[2,3-d]pyrimidin-4-ylamine		C₇H₆BrN₅	详情	详情
(IX)	31548	N-[6-bromo-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₇H₂₂BrN₅O₂	详情	详情
(X)	19649	1-vinylbenzene	100-42-5	C₈H₈	详情	详情
(XI)	31549	N-[2-[(2,2-dimethylpropanoyl)amino]-6-[(E)-2-phenylethenyl]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₂₅H₂₉N₅O₂	详情	详情
(XII)	31550	N-[2-[(2,2-dimethylpropanoyl)amino]-6-formylpyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide		C₁₈H₂₃N₅O₃	详情	详情
(XIII)	31554	3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₁H₁₁BrO	详情	详情
(XIV)	31552	3,4,5-trimethoxy-N-methylaniline; N-methyl-N-(3,4,5-trimethoxyphenyl)amine		C₁₀H₁₅NO₃	详情	详情
(XV)	31553	N-(2-[(2,2-dimethylpropanoyl)amino]-6-[[3,4,5-trimethoxy(methyl)anilino]methyl]pyrido[2,3-d]pyrimidin-4-yl)-2,2-dimethylpropanamide		C₂₈H₃₈N₆O₅	详情	详情

Extended Information